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Pharmaceutics
Volume 14
Issue 5
10.3390/pharmaceutics14051077
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Article

VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes

by
Alexandru Filippi
1,2,†,
Alina Constantin
1,†,
Nicoleta Alexandru
1,
Cristina Ana Mocanu
3,
Mihaela Loredana Vlad
4,
Ioana Madalina Fenyo
5,
Agneta Simionescu
6,
Dan Teodor Simionescu
6,
Ileana Manduteanu
3 and
Adriana Georgescu
1,*
1
Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania
2
Department of Biophysics, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
3
Department of Biopathology and Therapy of Inflammation, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania
4
Laboratory of Molecular and Cellular Pharmacology-Functional Genomics, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania
5
Laboratory of Gene Regulation and Molecular Therapies, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania
6
Department of Bioengineering, Clemson University, Clemson, SC 29634-0905, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Academic Editor: Fariba Ahmadizar
Pharmaceutics 2022, 14(5), 1077; https://doi.org/10.3390/pharmaceutics14051077
Received: 20 April 2022 / Revised: 10 May 2022 / Accepted: 13 May 2022 / Published: 17 May 2022
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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Abstract

The number and function of endothelial progenitor cells (EPCs) are reduced in diabetes, contributing to deteriorated vascular repair and the occurrence of cardiovascular complications. Here, we present the results of treating early diabetic dyslipidemic mice or dyslipidemic with disease-matched EPCs modified to overexpress VLA4 (VLA4-EPCs) as compared with the treatment of EPCs transfected with GFP (GFP-EPCs) as well as EPCs from healthy animals. Organ imaging of injected PKH26-stained cells showed little pulmonary first-pass effects and distribution in highly vascularized organs, with splenic removal from circulation, mostly in non-diabetic animals. Plasma measurements showed pronounced dyslipidemia in all animals and glycaemia indicative of diabetes in streptozotocin-injected animals. Echocardiographic measurements performed 3 days after the treatment showed significantly improved aortic valve function in animals treated with VLA4-overexpressing EPCs compared with GFP-EPCs, and similar results in the groups treated with healthy EPCs and VLA4-EPCs. Immunohistochemical analyses revealed active inflammation and remodelling in all groups but different profiles, with higher MMP9 and lower P-selectin levels in GFP-EPCs, treated animals. In conclusion, our experiments show that genetically modified allogeneic EPCs might be a safe treatment option, with bioavailability in the desired target compartments and the ability to preserve aortic valve function in dyslipidemia and diabetes. View Full-Text
Keywords: endothelial progenitor cells; integrin α4β1 (VLA4); aortic valve; dyslipidemia; diabetes endothelial progenitor cells; integrin α4β1 (VLA4); aortic valve; dyslipidemia; diabetes
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MDPI and ACS Style

Filippi, A.; Constantin, A.; Alexandru, N.; Mocanu, C.A.; Vlad, M.L.; Fenyo, I.M.; Simionescu, A.; Simionescu, D.T.; Manduteanu, I.; Georgescu, A. VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes. Pharmaceutics 2022, 14, 1077. https://doi.org/10.3390/pharmaceutics14051077

AMA Style

Filippi A, Constantin A, Alexandru N, Mocanu CA, Vlad ML, Fenyo IM, Simionescu A, Simionescu DT, Manduteanu I, Georgescu A. VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes. Pharmaceutics. 2022; 14(5):1077. https://doi.org/10.3390/pharmaceutics14051077

Chicago/Turabian Style

Filippi, Alexandru, Alina Constantin, Nicoleta Alexandru, Cristina A. Mocanu, Mihaela L. Vlad, Ioana M. Fenyo, Agneta Simionescu, Dan T. Simionescu, Ileana Manduteanu, and Adriana Georgescu. 2022. "VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes" Pharmaceutics 14, no. 5: 1077. https://doi.org/10.3390/pharmaceutics14051077

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